Monks S A, Leonardson A, Zhu H, Cundiff P, Pietrusiak P, Edwards S, Phillips J W, Sachs A, Schadt E E
Department of Statistics, Oklahoma State University, Stillwater, OK 74078-1056, USA.
Am J Hum Genet. 2004 Dec;75(6):1094-105. doi: 10.1086/426461. Epub 2004 Oct 21.
Combining genetic inheritance information, for both molecular profiles and complex traits, is a promising strategy not only for detecting quantitative trait loci (QTLs) for complex traits but for understanding which genes, pathways, and biological processes are also under the influence of a given QTL. As a primary step in determining the feasibility of such an approach in humans, we present the largest survey to date, to our knowledge, of the heritability of gene-expression traits in segregating human populations. In particular, we measured expression for 23,499 genes in lymphoblastoid cell lines for members of 15 Centre d'Etude du Polymorphisme Humain (CEPH) families. Of the total set of genes, 2,340 were found to be expressed, of which 31% had significant heritability when a false-discovery rate of 0.05 was used. QTLs were detected for 33 genes on the basis of at least one P value <.000005. Of these, 13 genes possessed a QTL within 5 Mb of their physical location. Hierarchical clustering was performed on the basis of both Pearson correlation of gene expression and genetic correlation. Both reflected biologically relevant activity taking place in the lymphoblastoid cell lines, with greater coherency represented in Kyoto Encyclopedia of Genes and Genomes database (KEGG) pathways than in Gene Ontology database pathways. However, more pathway coherence was observed in KEGG pathways when clustering was based on genetic correlation than when clustering was based on Pearson correlation. As more expression data in segregating populations are generated, viewing clusters or networks based on genetic correlation measures and shared QTLs will offer potentially novel insights into the relationship among genes that may underlie complex traits.
整合分子图谱和复杂性状的遗传信息，不仅是检测复杂性状数量性状基因座（QTL）的一种有前景的策略，也是了解哪些基因、通路和生物过程受特定QTL影响的一种有前景的策略。作为确定这种方法在人类中可行性的首要步骤，据我们所知，我们开展了迄今为止对分离人群中基因表达性状遗传力的最大规模调查。具体而言，我们测量了15个人类多态性研究中心（CEPH）家族成员淋巴母细胞系中23499个基因的表达。在所有基因中，发现2340个基因有表达，当使用错误发现率为0.05时，其中31%具有显著的遗传力。基于至少一个P值<.000005，检测到33个基因的QTL。其中，13个基因在其物理位置5 Mb范围内存在一个QTL。基于基因表达的Pearson相关性和遗传相关性进行层次聚类。两者都反映了淋巴母细胞系中发生的生物学相关活动，京都基因与基因组百科全书数据库（KEGG）通路中的一致性比基因本体论数据库通路中的更大。然而，基于遗传相关性聚类时比基于Pearson相关性聚类时在KEGG通路中观察到更多的通路一致性。随着分离人群中生成更多的表达数据，基于遗传相关性度量和共享QTL查看聚类或网络将为可能构成复杂性状基础的基因之间的关系提供潜在的新见解。
